tbuckley/cabot-search huggingface dataset:
A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth
Authors: Eugenio Morelli, Mariateresa Fulciniti, Mehmet K. Samur, Caroline F. Ribeiro, Leon Wert-Lamas, Jon E. Henninger, Annamaria Gullà, Anil Aktas-Samur, Katia Todoerti, Srikanth Talluri, Woojun D. Park, Cinzia Federico, Francesca Scionti, Nicola Amodio, Giada Bianchi, Megan Johnstone, Na Liu, Doriana Gramegna, Domenico Maisano, Nicola A. Russo, Charles Lin, Yu-Tzu Tai, Antonino Neri, Dharminder Chauhan, Teru Hideshima, Masood A. Shammas, Pierfrancesco Tassone, Sergei Gryaznov, Richard A. Young, Kenneth C. Anderson, Carl D. Novina, Massimo Loda, Nikhil C. Munshi
Journal: Blood (2022)

Long noncoding RNAs (lncRNAs) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell-growth dependency to lncRNA genes in multiple myeloma (MM) and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that an MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell-growth dependency acting in a microRNA- and DROSHA-independent manner. Lnc-17-92 provides a chromatin scaffold for the functional interaction between c-MYC and WDR82, thus promoting the expression of ACACA, which encodes the rate-limiting enzyme of de novo lipogenesis acetyl-coA carboxylase 1. Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent antitumor effects both in vitro and in vivo in 3 preclinical animal models, including a clinically relevant patient-derived xenograft NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.
Author Correction: Towards accurate and reliable resolution of structural variants for clinical diagnosis
Authors: Zhichao Liu, Ruth Roberts, Timothy R. Mercer, Joshua Xu, Fritz J. Sedlazeck, Weida Tong
Journal: Genome biology (2022)

Following the publication of the original paper [1], the authors reported a few errors.They would like to make the below corrections under the "Somatic Benchmarking" section, "Determination of sequencing technologies to improve SV detection" section, and Fig. 2.In "Somatic Benchmarking" section, "The HCC1395 cell line has been characterized with conventional genomics approaches such as cytogenetic analysis [49] and array-based comparative genomic hybridization [50], consisting of rich genetic variant types including ~40,000 SNVs, ~2000 small indels, CNAs covering over 50% of the genome, more than 250 complex genomic rearrangements [51], and an aneuploid genome and BRCAness [52]."To Supplementing WGS and WES, conventional array-based and cytogenetic-based genomics approaches [49,50] have been employed to characterize the HCC1395 cell line resulting in various genetic variant types, including a substantial number of SNV/small indels and complex SVs identified [35,51,52]."Moreover, the HCC1395 DNA was pooled with HCC1395BL DNA at different ratios to create a range of admixtures that mimicked tumor purity levels of 100%, 75%, 50%, 20%, 10%, 5%, and 0%."To Moreover, a series of admixtures were generated by titrating the HCC1395 and HCC1395BL DNA with different ratios to mimic the tumor purity levels from 0% to 100% [32]."Determination of sequencing technologies to improve SV detection" section The SEQC-II adopted multi-platform and multi-lab designs for a comprehensive assessment of reproducibility and accuracy of the detection of SVs.The SV working
Clarifying the Equivocal Diagnosis of Cervical Intraepithelial Neoplasia 2: Still a Work in Progress
Authors: Philip E. Castle, Nicolas Wentzensen
Journal: Journal of Clinical Oncology (2022)

Kremer et al 1 reported on a clinical trial (CONCERVE Study) to monitor women diagnosed with biopsyproven cervical intraepithelial neoplasia (CIN) grade 2 (CIN2) or 3 (CIN3; CIN2/3), rather than immediate treatment of the abnormality by surgical excision.The aim of the study was to reflect clinical practice to gain insight into the real-world impact of a wait-and-see policy for CIN2/3.They found a high percentage of CIN2/3 regressed clinically, defined as histologically confirmed absence of CIN2 or worse (CIN21) or an human papillomavirus (HPV)-negative cliniciancollected sample with normal cytology in case histology was absent and no histologic diagnosis of CIN21 during further follow-up.CIN2/3 was more likely to regress if it was negative for FAM19A4/miR124-2 methylation compared with those who were positive (74.7% v 51.4%, respectively, P 5 .014),leading the authors to suggest that FAM19A4/miR124-2 methylation testing could support a wait-and-see policy in women with CIN2/3.However, conflation of CIN2 and CIN3, study biases, and their definition of regression may lead to misinterpretation of their results.First, it is well established that CIN2 and CIN3 carry very different risks of invasive cancer.CIN2 is a poorly reproducible category that includes manifestations of HPV infections and some early abnormalities that is known to be highly regressive, especially in young women. 2Meanwhile, CIN3 is considered cervical precancer and presents a high risk of developing into invasive cervical cancer if untreated. 3Indeed, there is broad consensus that CIN31 (v CIN21) should be used as primary end point for studies of natural history, screening, and management.
Removing antenatal care from GPs is yet another blow to continuity of care
Authors: Daniel A Faller
Journal: BMJ (2022)

A short-cut review of the literature was carried out to establish whether inhaled methoxyflurane (Penthrox) is comparable or superior with a standard inhalational analgesia for the management of acute pain. Only two papers were identified as suitable for inclusion using the reported search strategy. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the best papers are tabulated. It is concluded that both methods of inhaled analgesia appear to be useful options for acute pain in the ED when compared with placebo. No evidence was found to suggest superiority of methoxypenflurane. International studies directly comparing the use of both drugs for in acute trauma are ongoing and will develop the evidence base.
Omicron BA.2 breakthrough infection enhances cross-neutralization of BA.2.12.1 and BA.4/BA.5
Authors: Alexander Muik, Bonny Gaby Lui, Maren Bacher, Ann-Kathrin Wallisch, Aras Toker, Andrew Finlayson, Kimberly Krüger, Orkun Ozhelvaci, Katharina Grikscheit, Sebastian Hoehl, Sandra Ciesek, Özlem Türeci, Ugur Sahin
Journal: Science Immunology (2022)

BNT162b2-vaccinated individuals after Omicron BA.1 breakthrough infection have strong serum-neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 variants of concern (VOCs) yet less against the highly contagious Omicron sublineages BA.4 and BA.5 that have displaced previous variants. Because the latter sublineages are derived from Omicron BA.2, we characterized serum-neutralizing activity of COVID-19 mRNA vaccine triple-immunized individuals who experienced BA.2 breakthrough infection. We demonstrate that sera of these individuals have broadly neutralizing activity against previous VOCs and all tested Omicron sublineages, including BA.2-derived variants BA.2.12.1 and BA.4/BA.5. Furthermore, applying antibody depletion, we showed that neutralization of BA.2 and BA.4/BA.5 sublineages by BA.2 convalescent sera is driven to a considerable extent by antibodies targeting the N-terminal domain (NTD) of the spike glycoprotein. However, neutralization by Omicron BA.1 convalescent sera depends exclusively on antibodies targeting the receptor binding domain (RBD). These findings suggest that exposure to Omicron BA.2, in contrast to BA.1 spike glycoprotein, triggers substantial NTD-specific recall responses in vaccinated individuals and thereby enhances the neutralization of BA.4/BA.5 sublineages. Given the current epidemiology with a predominance of BA.2-derived sublineages such as BA.4/BA.5 and rapidly ongoing evolution, these findings helped to inform development of our Omicron BA.4/BA.5-adapted vaccine.
Deep Morphology Learning Enhances <i>Ex Vivo</i> Drug Profiling-Based Precision Medicine
Authors: Tim Heinemann, Christoph Kornauth, Yannik Severin, Gregory I. Vladimer, Tea Pemovska, Emir Hadzijusufovic, Hermine Agis, Maria-Theresa Krauth, Wolfgang R. Sperr, Peter Valent, Ulrich Jäger, Ingrid Simonitsch-Klupp, Giulio Superti-Furga, Philipp B. Staber, Berend Snijder
Journal: Blood Cancer Discovery (2022)

Abstract Drug testing in patient biopsy-derived cells can identify potent treatments for patients suffering from relapsed or refractory hematologic cancers. Here we investigate the use of weakly supervised deep learning on cell morphologies (DML) to complement diagnostic marker-based identification of malignant and nonmalignant cells in drug testing. Across 390 biopsies from 289 patients with diverse blood cancers, DML-based drug responses show improved reproducibility and clustering of drugs with the same mode of action. DML does so by adapting to batch effects and by autonomously recognizing disease-associated cell morphologies. In a post hoc analysis of 66 patients, DML-recommended treatments led to improved progression-free survival compared with marker-based recommendations and physician's choice–based treatments. Treatments recommended by both immunofluorescence and DML doubled the fraction of patients achieving exceptional clinical responses. Thus, DML-enhanced ex vivo drug screening is a promising tool in the identification of effective personalized treatments. Significance: We have recently demonstrated that image-based drug screening in patient samples identifies effective treatment options for patients with advanced blood cancers. Here we show that using deep learning to identify malignant and nonmalignant cells by morphology improves such screens. The presented workflow is robust, automatable, and compatible with clinical routine. This article is highlighted in the In This Issue feature, p. 476
Artificial Intelligence for Contrast-Free MRI: Scar Assessment in Myocardial Infarction Using Deep Learning–Based Virtual Native Enhancement
Authors: Qiang Zhang, Matthew K. Burrage, Mayooran Shanmuganathan, Ricardo A. Gonzales, Elena Lukaschuk, Katharine E. Thomas, Rebecca Mills, Joana Leal Pelado, Chrysovalantou Nikolaidou, Iulia A. Popescu, Yung P. Lee, Xinheng Zhang, Rohan Dharmakumar, Saul G. Myerson, Oliver Rider, Keith M. Channon, Stefan Neubauer, Stefan K. Piechnik, Vanessa M. Ferreira
Journal: Circulation (2022)

Background: Myocardial scars are assessed noninvasively using cardiovascular magnetic resonance late gadolinium enhancement (LGE) as an imaging gold standard. A contrast-free approach would provide many advantages, including a faster and cheaper scan without contrast-associated problems. Methods: Virtual native enhancement (VNE) is a novel technology that can produce virtual LGE-like images without the need for contrast. VNE combines cine imaging and native T1 maps to produce LGE-like images using artificial intelligence. VNE was developed for patients with previous myocardial infarction from 4271 data sets (912 patients); each data set comprises slice position-matched cine, T1 maps, and LGE images. After quality control, 3002 data sets (775 patients) were used for development and 291 data sets (68 patients) for testing. The VNE generator was trained using generative adversarial networks, using 2 adversarial discriminators to improve the image quality. The left ventricle was contoured semiautomatically. Myocardial scar volume was quantified using the full width at half maximum method. Scar transmurality was measured using the centerline chord method and visualized on bull’s-eye plots. Lesion quantification by VNE and LGE was compared using linear regression, Pearson correlation ( R ), and intraclass correlation coefficients. Proof-of-principle histopathologic comparison of VNE in a porcine model of myocardial infarction also was performed. Results: VNE provided significantly better image quality than LGE on blinded analysis by 5 independent operators on 291 data sets (all P &lt;0.001). VNE correlated strongly with LGE in quantifying scar size ( R , 0.89; intraclass correlation coefficient, 0.94) and transmurality ( R , 0.84; intraclass correlation coefficient, 0.90) in 66 patients (277 test data sets). Two cardiovascular magnetic resonance experts reviewed all test image slices and reported an overall accuracy of 84% for VNE in detecting scars when compared with LGE, with specificity of 100% and sensitivity of 77%. VNE also showed excellent visuospatial agreement with histopathology in 2 cases of a porcine model of myocardial infarction. Conclusions: VNE demonstrated high agreement with LGE cardiovascular magnetic resonance for myocardial scar assessment in patients with previous myocardial infarction in visuospatial distribution and lesion quantification with superior image quality. VNE is a potentially transformative artificial intelligence–based technology with promise in reducing scan times and costs, increasing clinical throughput, and improving the accessibility of cardiovascular magnetic resonance in the near future.
Correction: Rapid molecular diagnostics of tuberculosis resistance by targeted stool sequencing
Authors: Doctor B. Sibandze, Alexander Kay, Viola Dreyer, Welile Sikhondze, Qiniso Dlamini, Andrew DiNardo, Godwin Mtetwa, Bhekumusa Lukhele, Debrah Vambe, Christoph Lange, Muyalo Glenn Dlamini, Tara Ness, Rojelio Mejia, Barbara Kalsdorf, Jan Heyckendorf, Martin Kuhns, Florian P. Maurer, Sindisiwe Dlamini, Gugu Maphalala, Stefan Niemann, Anna Mandalakas
Journal: Genome Medicine (2022)
DNA methylation underpins the epigenomic landscape regulating genome transcription in Arabidopsis
Authors: Lun Zhao, Qiangwei Zhou, Li He, Li Deng, Rosa Lozano-Duran, Guoliang Li, Jian-Kang Zhu
Journal: Genome biology (2022)

It is challenging to determine the effect of DNA methylation on the epigenetic landscape and the function in higher organisms due to the lack of DNA methylation-free mutants.
Inflammation and Clinical Decline After Adjuvant Chemotherapy in Older Adults With Breast Cancer: Results From the Hurria Older Patients Prospective Study
Authors: Jingran Ji, Can-Lan Sun, Harvey J. Cohen, Timothy Synold, Hyman Muss, Mina S. Sedrak
Journal: Journal of Clinical Oncology (2022)

Older breast cancer survivors are at increased risk of clinical decline after adjuvant chemotherapy. This study aimed to evaluate whether inflammatory markers assessed before adjuvant chemotherapy are associated with chemotherapy-induced clinical decline in a population of fit older adults with breast cancer.
Reply to P. Castle et al
Authors: Johannes Berkhof, Stefanie Dick, Wieke Kremer, Maaike Bleeker, Chris Meijer
Journal: Journal of Clinical Oncology (2022)

We thank Castle and Wentzensen 1 for their comments that enable us to clarify several points.Castle and Wentzensen 1 suggest that our study would not reflect real-world practice because cervical intraepithelial neoplasia (CIN) 3 is almost universally treated and the study contains restrictive inclusion criteria on the basis of lesion size and history of CIN11.Furthermore, they suggest that regression might be a misclassified human papillomavirus (HPV) infection, rather than precancer, that ultimately resolved and women with CIN1 might have type-specific HPV persistence and hence be falsely reassured against their cancer risk.
<i>Vital Signs:</i> Use of Recommended Health Care Measures to Prevent Selected Complications of Sickle Cell Anemia in Children and Adolescents — Selected U.S. States, 2019
Authors: Laura A. Schieve, Gretchen M. Simmons, Amanda B. Payne, Karon Abe, Lewis L. Hsu, Mary Hulihan, Shammara Pope, Sarah Rhie, Brandi Dupervil, W. Craig Hooper
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Introduction: Sickle cell disease (SCD), a group of inherited blood cell disorders that primarily affects Black or African American persons, is associated with severe complications and a >20-year reduction in life expectancy.In 2014, an expert panel convened by the National Heart, Lung, and Blood Institute issued recommendations to prevent or reduce complications in children and adolescents with the most severe SCD subtypes, known as sickle cell anemia (SCA); recommendations included 1) annual screening of children and adolescents aged 2-16 years with transcranial Doppler (TCD) ultrasound to identify those at risk for stroke and 2) offering hydroxyurea therapy to children and adolescents aged ≥9 months to reduce the risk for several life-threatening complications. Methods: Data from the IBM MarketScan Multi-State Medicaid Database were analyzed.TCD screening and hydroxyurea use were examined for 3,352 children and adolescents with SCA aged 2-16 years and continuously enrolled in Medicaid during 2019.Percentage change during 2014-2019 and variation by health subgroups were assessed.Analyses were stratified by age.Results: During 2014-2019, TCD screening increased 27% among children and adolescents aged 10-16 years; hydroxyurea use increased 27% among children aged 2-9 years and 23% among children and adolescents aged 10-16 years.However, in 2019, only 47% and 38% of children and adolescents aged 2-9 and 10-16 years, respectively, had received TCD screening and 38% and 53% of children and adolescents aged 2-9 years and 10-16 years, respectively, used hydroxyurea.For both prevention strategies, usage was highest among children and adolescents with high levels of health care utilization and evidence of previous complications indicative of severe disease.Conclusion and Implications for Public Health Practice: Despite increases since 2014, TCD screening and hydroxyurea use remain low among children and adolescents with SCA.Health care providers should implement quality care strategies within their clinics and partner with patients, families, and community-based organizations to address barriers to delivering and receiving recommended care.
Reactivation of a silenced <it>H19</it> gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation
Authors: Catherine A Lynch, Benjamin Tycko, Timothy H Bestor, Colum P Walsh
Journal: Molecular Cancer (2002)

The active copy of the imprinted gene H19 is turned off by inappropriate methylation in several pediatric tumors including Wilms' Tumour and embryonal rhabdomyosarcoma. H19 controls in cis the linked Insulin-like Growth Factor 2 (IGF2) gene, encoding an important growth factor. Recent work has suggested that methylation of a gene may lead to deacetylation of its associated histones and that silenced genes can be reactivated by increasing histone acetylation levels. Treatment of a rhabdomyosarcoma cell line which has a silent, methylated H19 gene with histone deacetylase (HDAC) inhibitors under conditions which gave maximal hyperacetylation of histone 4, both globally and at the H19 gene itself could not reactivate H19 or affect the active Insulin-like Growth Factor 2 (IGF2) gene, but caused clear up-regulation of the Tissue-type Plasminogen Activator (TPA) gene, a non-imprinted gene known to respond to changes in histone acetylation. In contrast, mild treatment of the cells with the methylation inhibitor 5-AzaC-2'-deoxycytidine (AzaC) on its own was able to reactivate H19. Combining AzaC treatment with HDAC inhibitors gave a reduced rather than enhanced reactivation. These findings were confirmed in mouse primary liver and kidney explants which maintain normal imprinting, where we also found that the silent Igf2 gene could not be reactivated by HDAC inhibitors. These results suggest that DNA methylation rather than histone acetylation is the primary determinant of silencing of H19 in rhabdomyosarcoma.
Oral Contraceptives, Chlamydia trachomatis Infection, and Pelvic Inflammatory Disease
Authors: A. Eugene Washington
Journal: JAMA (1985)

Management of pelvic inflammatory disease (PID) and decisions about contraception are being influenced by reports that oral contraceptives decrease the risk of PID. To evaluate the validity of this association, we have examined published epidemiologic evidence and reviewed relevant information from other disciplines. Current information does not permit the generalization that oral contraceptives protect against all forms of PID. Most studies conducted (1) have been limited to hospitalized women, who represent less than 25% of all PID cases and are likely to have relatively severe forms of the disease, and (2) have failed to distinguish between gonococcal and nongonococcal PID. While oral contraceptives may provide some protection against gonococcal PID, no basis exists for assuming similar protection is provided against chlamydial PID. In fact, epidemiologic and biologic evidence suggests that infection with<i>Chlamydia trachomatis</i>, the leading cause of nongonococcal PID, is enhanced by oral contraceptives. We judge the conclusion that oral contraceptives protect against all PID to be premature, and urge caution in its application in health policy and clinical decisions. (<i>JAMA</i>1985;253:2246-2250)
Early-Phase Changes in Serum Free Fatty Acid Levels After Glucose Intake Are Associated With Type 2 Diabetes Incidence: The Hiroshima Study on Glucose Metabolism and Cardiovascular Diseases
Authors: Nobuo Sasaki, Ryo Maeda, Ryoji Ozono, Kenichi Yoshimura, Yukiko Nakano, Yukihito Higashi
Journal: Diabetes Care (2022)

Experimental studies suggest that excess serum free fatty acid (FFA) levels result in impaired glucose metabolism. This study investigated the relationship between changes in serum FFA levels after glucose intake and type 2 diabetes risk.This observational study included 6,800 individuals without diabetes who underwent a 75-g oral glucose tolerance test. Serum FFA levels were measured before and 30 and 60 min after glucose intake. The percentages of changes in serum FFA levels from 0 to 30 and from 30 to 60 min were compared, and a low rate of change in FFA levels was determined using the receiver operating characteristic curve analysis.Over a mean 5.3-year follow-up period, 485 participants developed type 2 diabetes. After adjusting for plasma glucose levels and indices of insulin resistance and β-cell function, low rates of change in FFA levels at 0-30 min (adjusted odds ratio [aOR] 1.91; 95% CI 1.54-2.37) and 30-60 min (aOR 1.48; 95% CI 1.15-1.90) were associated with the incidence of type 2 diabetes. Stratified analysis revealed that the low rate of change in FFA levels at 30-60 min (aOR 1.97; 95% CI 1.05-3.69) was associated with the incidence of type 2 diabetes even in participants with normal fasting glucose levels or glucose tolerance.Changes in serum FFA levels within the 1st h after glucose intake could be a primary predictor of type 2 diabetes. This change may occur prior to the onset of impaired glucose metabolism.
The effects of diversion of intestinal contents on the progress of Crohn's disease of the large bowel
Authors: J. H. Burman, H. Thompson, W. T. Cooke, J. A. Williams
Journal: Gut (1971)

This study shows that faecal diversion by ileostomy or colostomy results in an improvement in the patient9s general health which is substantiated by the haematological and biochemical findings. However, in the bowel distal to the diversion there is always histological evidence of mucosal and transmural disease and complications such as fistulae may still occur. In only two patients (7%) was restoration of bowel continuity successful.